Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation

Abstract

Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies such as Alzheimer’s disease. A central unanswered question is why tau becomes progressively hyperphosphorylated. Here, we show that tau phosphorylation is governed by interdependence— a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic assessment of site interdependence identified distinct residues (threonine-50, threonine-69, and threonine-181) as master sites that determine propagation of phosphorylation at multiple epitopes. CRISPR point mutation and expression of human tau in Alzheimer’s mice showed that site interdependence governs physiologic and amyloid-associated multi-site phosphorylation and cognitive deficits, respectively. Combined targeting of master sites and p38α, the most central tau kinase linked to interdependence, synergistically ablated hyperphosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies.

A systematic review and meta-analysis of tau phosphorylation in mouse models of familial Alzheimer’s disease

“…It is thus, plausible that the progressive reduction in the magnitude of tau hyperphosphorylation at the CT domain, as observed here in 1-13-month-old 5xFAD mice, is driven by the advanced phases of amyloidosis, while the progressive increase in PR phosphorylated tau, as observed in 3-13-month-old APP swe / PSEN1 dE9 mice, is associated with stages of escalating Aβ pathology. Although speculative, this interpretation is in line with data which show that markers of PR domain phosphorylated tau exhibit close correlations with early Aβ pathology (Mattsson-Carlgren et al, 2020; Ossenkoppele et al, 2021), while CT domain phosphorylated tau is generally considered as a late marker in the AD continuum (Neddens et al, 2018; Stefanoska et al, 2022; Zhou et al, 2006). It is also important to note that longitudinal studies of soluble tau biomarkers in the cerebrospinal fluid (CSF) of familial AD patients, show that the extent of phosphorylation at the PR domain of tau increases significantly in the presence of amyloid pathology, but then decreases as the disease progresses (Barthelemy et al, 2020; Fagan et al, 2014; McDade et al, 2018).…”

Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS

“…Further, T181 was recently reported as a "master site" for tau phosophorylation. 31 However, the fact that only the pT181/T181 ratio was affected by suvorexant, and not pS202/S202 or pT217/T217, adds uncertainty to the results. Additional studies are needed to replicate this result and test if amyloid-positive individuals with hyperphosphorylated tau who are chronically treated with suvorexant have reduced tau phosphorylation at sites other than T181.…”

“…Longer sampling times may have shown a decrease in the pS202/S202 ratio as the suvorexant 20 mg was increasingly separating from placebo at hour 36. Further, T181 was recently reported as a “master site” for tau phosophorylation 31 . However, the fact that only the pT181/T181 ratio was affected by suvorexant, and not pS202/S202 or pT217/T217, adds uncertainty to the results.…”

“…Starting from a baseline of 23% to 26%, the pT181/T181 ratio decreased 2% to 4% (a relative reduction of 10-15%) over the first 7 hours after receiving suvorexant 20 mg at 21:00 (hour 1) and remained lower for hours from 10:00-12:00 (hours 14- ). The ratio then increased to approximately the level of the placebo group at hour 24 and then decreased again after participants received the second dose of suvorexant 20 mg from 22:00 to 08:00 (hours [26][27][28][29][30][31][32][33][34][35][36]. The area under the curve (AUC) of percent change from hour 0 for pT181/T181 across hours 0 to 36 was also significantly reduced in the suvorexant 20 mg group compared to placebo.…”

Recent Advancements in the Early Diagnosis and Treatment of Alzheimer's Disease

“…[39][40][41] Tau is phosphorylated by several tau kinases including glycogen-synthase kinase-3𝛽 (GSK-3𝛽), cyclin-dependent protein kinase 5 (CDK5), and its activator p25, cAMP-dependent protein kinase (PKA), mitogen-activated protein kinases (MAPK), calcium-calmodulin-dependent kinase-II (CaMK II), and microtubule affinity-regulating kinase (MARK), commonly at the proline (P) and serine (S) or threonine (T) residues. [42][43][44] Abnormally hyperphosphorylated tau protein aggregates more easily to form insoluble paired helical filaments (PHF), which then twist to form neurofibrillary tangles (NFTs) after further aggregation and thickening. In most cases, the ability of abnormally hyperphosphorylated tau protein to bind to tubulin will be reduced.…”